Impact of achondroplasia on Latin American patients: a systematic review and meta-analysis of observational studies

Background Achondroplasia (ACH), the most common form of disproportionate short stature, is caused by a pathogenic variant in the fibroblast growth factor receptor 3 gene. Recent advances in drug therapy for ACH have highlighted the importance of elucidating the natural history and socioeconomic burden of this condition. Recognition that there are many potential issues for the patient with ACH is the first step in planning cost-effective interventions in Latin America (LATAM), a vast geographic territory comprising countries with multicultural characteristics and wide socioeconomic differences. We conducted a systematic literature review to characterize the impact of ACH on affected individuals and on healthcare resources in LATAM countries. Methods Searches of the global medical literature as well as regional and local medical literature up to August 2020. Observational studies on patients with ACH from any LATAM country. Pairs of reviewers independently screened eligible articles, extracted data from included studies, and assessed their risk of bias. Results Fifty-three unique studies (28 case series and cross-sectional studies and 25 case reports) including data on 1604 patients were eligible. Of these studies, 11 had data available for meta-analysis. Both premature mortality and all-cause mortality in the pooled studies was 15% [95% Confidence Interval (CI) 1.0E−3 to 0.47; I2 = 82.9%, p = 0.0029; three studies, n = 99 patients]. Frequency of cardio-respiratory-metabolic disorders was 17% [95% CI 0.04–0.37; I2 = 90.3%, p < 0.0001; four studies, n = 230 patients]; nervous system disorders was 18% [95% CI 0.07–0.33; I2 = 84.6%, p < 0.0001; six studies, n = 262 patients]; ear, nose, throat and speech disorders was 32% [95% CI 0.18–0.48; I2 = 73.4%, p = 0.0046; five studies, n = 183 patients]; and spinal issues including stenosis, compression and associated pain was 24% [95% CI 0.07–0.47; I2 = 91.3%, p < 0.0001; five studies, n = 235 patients]. Conclusions There is currently evidence of high clinical burden in ACH patients in LATAM countries. Establishing the impact of ACH provides the necessary foundation for planning tailored and effective public health interventions. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-021-02142-3.

However, data from the Latin American Collaborative Study of Congenital Malformations (ECLAMC) estimates a similar incidence in non-LATAM countries of 0.43 in 10,000 or 0.45 in 10,000 [8] In LATAM countries, ACH is often assumed to be compatible with a healthy and productive life. However, current evidence indicates that ACH is associated with a range of medical complications including obstructive sleep apnea, spinal stenosis, chronic pain, and cervicomedullary compression with subsequent risk of high surgical burden and death [9,10]. In addition, ACH patients may experience a number of socioeconomic issues such as social isolation, lower self-esteem, less education, and lack of employment opportunities [11][12][13][14][15]. Management of all these complications can be challenging as it requires multidisplinary intervention.
Recognition that there are many potential issues for the patient with ACH is the first step in planning costeffective interventions in LATAM, a vast geographic territory comprising countries with distinct cultures, socioeconomic structures, and public healthcare systems. However, due to the paucity of published studies on LATAM patients with ACH, particularly in the English-language medical literature, there is currently limited understanding of the impact of ACH on affected individuals and on healthcare systems in this region of the world. Moreover, of the published studies, the majority have stemmed from single centres with small patient cohorts. Furthermore, despite the growing evidence in the English-language medical literature of the clinical and psychosocial burden among patients with ACH, published studies are not exclusively based on LATAM populations and therefore the findings may not necessarily be generalizable to LATAM patients, and the experiences of living with ACH may not be the same across different regions of the world. We therefore conducted a systematic literature review and metaanalysis to better specifically characterize the impact of ACH in LATAM countries at the level of patientimportant outcomes as well as at the economic (socioeconomic, healthcare utilization) level.

Materials and methods
Our review followed recommendations for systematic reviews and meta-analyses (PRISMA) [16] of observational studies in epidemiology (MOOSE) [17] statements. This systematic review was registered in the PROSPERO (International Prospective Register of Systematic Reviews) database under the number CRD42020204963.

Eligibility criteria
We included any epidemiological observational study (e.g., cohort, case-control, nested case-control, crosssectional studies, prospective case series, case report) on patients with ACH from any LATAM country (e.g., Brazil, Argentina, Colombia, Mexico, Costa Rica, Peru), regardless of whether they reported our pre-defined patient-important outcomes and/or economic burden outcomes defined below. A diagnosis of ACH in patients in the included studies was based on genetic confirmation and/or clinical diagnosis of ACH (clinical examination and/or radiological assessment).
We excluded studies that evaluated patients with only hypochondroplasia as well as commentaries, reviews, off-topic studies, and those with co-occurrence of ACH and another syndrome.
For patient-important outcomes, we were interested in investigating the following: • Mortality: • Premature mortality defined as sudden death within 1 year of age; • All-cause mortality; and • Cardiovascular mortality.
• Humanistic: • Psychosocial disorders: depression, anxiety, bullying, isolation, hopelessness, somatization, humiliation, stigma, perception about their psychosocial life, etc., measured by non-validated and validated questionnaires as defined by the included studies; • Delayed self-care skills (e.g., toileting, cup-drinking); • Suicide attempts, and/or suicide rates; and • Social adaptation challenges; • Impact of the disease on patient and/or caregiver health-related quality of life, activities of daily living, work productivity, education, employment, social, and so forth; and • Quality of life measured by non-validated and validated questionnaires, as defined by the included studies, such as the Brief Pain Inventory-Short Form (BPI-SF) Questionnaire, the Quality of Life Short Stature Youth (QoLiSSY) Questionnaire, and the Pediatric Quality of Life Inventory (Ped-sQL).
At the economic level, we were interested in investigating the following outcomes: • Socioeconomic burden (e.g., securing employment) measured by non-validated and validated questionnaires, as defined by the included studies such as the Work and Productivity and Activity Impairment (WPAI-SHP). • Environmental burden: • Lack of equipment, furniture, toys, shoes, etc., matching anthropometric limitations; • Limitation of physical access to transportation modalities; • Adaptation to standard transport equipment and; • Challenges in physical activity.
• Health economic impact: • Direct and/or indirect costs, treatment costs, health care resource use, cost of comedications, hospitalizations.

Data source and searches
Using Medical Subject Headings (MeSH) based on the terms "achondroplasia" and "skeletal dysplasia" (Additional file 1: We also conducted the search using both Spanish and English terms in the regional and local medical literature using Latin American and Caribbean Health Sciences Literature (LILACS, 1982 to August 2020), Scientific Electronic Library Online (SciELO, 1997 to August 2020), SciVerse Scopus via Elsevier (to August 2020), the Spanish Bibliographic Index of the Health Sciences (IBECS, 1983 to August 2020), National Bibliography in Health Sciences Argentina (BINACIS, to August 2020), Caribbean Health Sciences Literature (MedCarib, to August 2020), National Medical Sciences Information Center of Cuba (CUMED, to August 2020), and the Brazilian Bibliography of Dentistry (BBO to August 2020). The date of the last search was August 18, 2020.
We also searched the gray literature including Pro-Quest Dissertations & Theses Global (1989 to 2020), the National Health Surveillance Agency (ANVISA), Brazilian Digital Library of Theses and Dissertations (BDTD), Latindex Redalyc Latam, Mexico National Institute of Pediatrics website, and conference proceedings. In addition, reference lists of relevant primary studies were hand searched and experts in the field were contacted to obtain additional unpublished data.
We did not impose any language or year restrictions. The search strategy was adapted for each database to achieve more sensitivity. Duplicate records across databases were removed.

Selection of studies
Reviewers independently screened all titles and abstracts identified by the literature search using online software Covidence (https:// www. covid ence. org), obtained full-texts articles of all potentially relevant studies, and evaluated them against the eligibility criteria. Reviewers resolved disagreements by discussion or, if necessary, with third party adjudication. We also considered studies reported as abstracts; however, those that did not contain data to extract were excluded from the review. We recorded the selection process and completed a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram (Fig. 1).

Data extraction
Reviewers independently extracted the following data using a pre-standardized data extraction form: (1) first author and year of publication; (2) country; (3) study design; (4) scenario; (5) age, gender, and body mass index (BMI); (6) number of patients; (7) eligibility criteria; and (8) patient-important and economic outcomes, if available. We avoided double counting of participants where there were multiple publications in the same population. If there was more than one published report of the same group of patients, the articles were analysed to verify whether they reported different outcomes. If they presented the same outcomes, we extracted the data from the most complete article. For studies that did not report BMI but provided height and weight we calculated this variable.

Risk of bias assessment
For cohort and case-control studies, we planned to assess risk of bias with a modified version of the Ottawa-Newcastle instrument [18] that includes confidence in assessment of exposure and outcome; however, there was no included study classified as either cohort or case-control study.
For cross-sectional studies, we assessed risk of bias with the AXIS tool [19], though we excluded some domains not applied to our review. For case series and case reports, we used the single tool from the Joanna Briggs Institute (JBI) critical appraisal checklist for case reports [20]. However, in our view, the structure of the response options in both AXIS and JBI instruments leaves much to be desired. Therefore, we modified the response options to "definitely yes" (low risk of bias), "partially yes" (not all information needed available), "unclear" (no information to judge), and "definitely no" (high risk of bias), and applied it to our form for risk of bias in both cross-sectional and case series studies.

Data synthesis and statistical analysis
We performed a systematic review of clinical studies with pooled analysis of proportions [21,22], using the method of Stuart-Ord (inverse double arcsine square root).
Only case series and cross-sectional studies were considered for any quantitative analysis; case reports were excluded. We analyzed all outcomes as dichotomous variables with their respective confidence intervals (CI) of 95%. Since we expected that there were both clinical and methodological differences among the included studies, a random-effects model [23] was used to perform the pooled analysis of proportions. A statistically significant difference between two interventions required that their combined 95% CIs did not overlap [21,22]. We calculated weighted mean and pooled measure of variability (standard deviation) for quality of life in the Cervan et al., 2008 [24] study as this study presented data of quality of life (QoL) for physical, psychological, social, environmental domains. The meta-analysis was performed with the StatsDirect software, version 2.8.0. (StatsDirect Ltd, Altrincham, Cheshire, UK).
Because of the very sparse data on this rare condition, when there was more than one report of the same type of burden outcome in the same study, we obtained the mean or median value from the subtype of outcome for the proportional meta-analysis to avoid selection bias. For example, on cardio-respiratory-metabolic disorders outcome, one study could report excessive snoring (number of events per number of total patients, 1/39), obesity (4/39), adenotonsillectomy (5/39), sleep disturbance (21/39), as well as sleep apnea (39/39). In this example, the median value used would be adenotonsillectomy (5/39).

Subgroup and sensitivity analyses
We planned to perform subgroup analyses if there was a minimum of two studies in each category: (1) LATAM countries (e.g., Brazil versus Argentina); (2) adults versus children; however, there was an insufficient number of studies to allow for these assessments.
We performed a sensitivity analysis to explore causes of heterogeneity of the results, excluding studies according to study designs (i.e., case series versus cross-sectional studies).

Heterogeneity assessment and publication bias
We investigated heterogeneity using the chi-square test and the I 2 statistic [25]. An I 2 value of 0-40%, 30-60%, 50-90% or 75-100% was interpreted as not important, moderate, substantial or considerable heterogeneity, respectively, and significance was assumed when I 2 was > than 50% with a p < 0.1.
There was an insufficient number of studies (at least 10 or more) to allow for assessment of publication bias through visual inspection of funnel plots.

Study selection
Our initial searches identified 4,149 citations. All were from electronic databases, except for ten studies identified through grey literature. After we removed duplicates from different databases, we retained 3,903 potentially relevant articles for further assessment. After reading titles and abstracts, 87 articles were retrieved as full text for further assessment. After screening the full texts, we included 53 clinical studies with one further publication. We excluded 32 studies after reviewing the full papers. The reasons for exclusion are listed in the PRISMA flow diagram (Fig. 1). The total number of included studies is 53 with one further publication, and from these 11 contributed to meta-analysis.

Cardio-respiratory-metabolic disorders
The pooled proportion for cardio-respiratory-metabolic disorders was 17% [95% CI 0.04 to 0.37; I2 = 90.3%, p < 0.0001] from four studies [5,37,56,75,76] with a total of 230 patients (Fig. 3). There was significant statistical heterogeneity in the analyses. The outcomes used to calculate the mean or median of the cardio-respiratorymetabolic disorders among the studies included in the analysis were: adenotonsillectomy [5]; apnea followed by death [37]; pneumonia [56]; apnea index slightly and moderately increased [75]; desaturations during sleep [75]; and apnea [75]. There was no outcome directly related to cardiac to be included in this category.

Psychosocial disorders
The pooled proportion for psychosocial complications was 19% [95% CI 0.02 to 0.48; I2 = 80.8%, p = 0.0054] from three studies [5,66,70] with a total of 66 patients (Fig. 3). There was significant statistical heterogeneity in the analyses. The outcomes used to calculate the mean or median of the psychosocial disorders among the studies included in the analysis were: depression [5], perception of their body image [66], and mild somatization [70].

Descriptive analysis
Four studies [38,58,69,75,76] reported on economic burden outcomes. Gomez et al., 2017 [58] reported on the adaptation of shoes for the ACH patients and the costs associated with the anthropometric and baropodometric analyses of the foot. This study addressed the design of a footwear system that fulfills form, function and usage of eight persons with ACH patients. The most relevant information was that footwear should have a low heel (about 2 cm) as there is a greater risk of falling due to the instability associated with wearing higher heels (7 1⁄2 cm and above), considering the lower center of gravity for ACH patients; however, patients want to have comfort and elegant heels and shoes ( Table 1).
The Lima, 2019 [38] study sought to identify the consequences of stigmatization on social life, including work. The results indicate that people with ACH experience humiliation and disrespect due to associations made with the stereotype built about them. The authors found this stereotype is commonly used by comedians for entertainment purposes (Table 1) (Table 1). Patients reported that while physical activities can be difficult to perform [75,76], though the regular practice of physical activity improves their self-esteem and confidence which in turn contributes to their sense of social inclusion [69].
None of the included studies reported on the following patient-important outcomes: suicide attempts, and suicide rates; impact of the disease on caregivers, such as health-related quality of life, activities of daily living, work productivity, education, employment, social, and so forth; and social adaptation challenges. Furthermore, none of the included studies reported on the following economic burden outcomes: limitation of physical access to transportation modalities; and adaptation to standard transport equipment.
We have now applied a methodology [21,22] to evaluate the proportions of clinical burden outcomes in the LATAM ACH population. The proportions of pooled case series and cross-sectional studies were consistent with results from only pooled cross-sectional studies in the outcomes of nervous system disorders and spinal issues including stenosis, compression and associated pain, meaning that the assumed proportions lie in a high probability of a true value. To the best of our knowledge, this is the first study to clearly demonstrate the burden of LATAM ACH patients, an observation that should be taken into account in regional health policy debates regarding management of ACH disease. Of note, while limb lengthening procedures are frequently performed on ACH patients in LATAM, we were not able to find any data on these procedures in the included studies.

Strengths and limitations
Strengths of our review include a comprehensive search; assessment of eligibility, risk of bias and data abstraction independently and in duplicate; and an assessment of risk of bias that included a sensitivity analysis addressing homogeneity of study designs.
The primary limitation of our study is related to the rare disease nature of ACH. The population available to study was limited and the study designs presented some flaws. Another limitation is that our analysis demonstrates a significant heterogeneity (I 2 ) in all studied clinical burden outcomes. Explanations for this heterogeneity could be both clinical and methodological diversities. The studies differed considerably in their mean age of patient selection, study designs (i.e., case series, cross-sectional, and case reports), and type of burden outcomes (e.g., nervous system disorders, one study could report hydrocephalus, while another reports epilepsy).
Furthermore, out of the 53 clinical studies we were only able to include data in the meta-analysis from 11 of them (20.4%). The majority of the studies were difficult to decipher, and they did not provide all burden pre-defined outcomes.
A further limitation was the insufficient number of studies, which prevented completing statistical analyses that had initially been planned. We were unable to assess publication bias because there were less than 10 eligible studies addressing the same outcome in a meta-analysis. Subgroup analyses on LATAM countries (e.g., Brazil versus Argentina), and adults versus children were not possible since minimal criteria were not met (i.e., at least four studies available, with at least two in each sub-group).
A sensitivity analysis pooling all included studies (i.e., case series and cross-sectional studies) compared with pooling only the cross-sectional studies was only possible for nervous system disorders and spinal issues outcomes. No difference was found in the proportion of overlap CIs between both analyses.

Relation to prior research
Unfortunately, there is a dearth of information on LATAM patients in both non-English and Englishlanguage medical literature on ACH. While we found a 15% mortality rate in our review, with a wide-ranging prevalence from 0.1 to 47%, a multicenter study of mortality in ACH [77] that studied 855 USA patients presented an overall mortality rate of 99% per 1,000 person years, with an absolute number of deaths of 12 patients (n = 5, toddlers; n = 2, young children; and n = 5, young adulthood). The authors of the clinical study also found that the infant mortality rate was 3.2/1,000 person years. Although only three studies [37,56,72] contributed to our data on mortality, only one of them [56] reported the mean age of the population as 3.07 years old. Therefore, in our systematic review, 33.33% of the mortality data is contributed from predominantly children with a mean age of three years. Another two studies have estimated the maximal risk of deaths in the first year of life as 7.5% [2,9]; this high percentage may also be explained due to the absence of special care and surgical intervention.
Furthermore, an additional two studies [78,79] identified in the literature corroborate with our findings showing that motor delays are common in the ACH population. In our review, we found a prevalence of nervous system disorders, which encompassed motor delay, of 26% with a reasonable CI ranging from 12 to 44%. A high prevalence of ear, nose, and throat disorders (32%) and spinal issues (26%) were found in our review which is consistent with other studies indicating that middle ear dysfunction [80] and spinal stenosis [81] are highly common in both children and adults with ACH.

Conclusions
LATAM ACH patients presented a high prevalence of clinical complications, although the possibility of residual confounding due to lack of adequate reports in this population and high heterogeneity in the analysis cannot be ruled out. This study also highlights the need to address well-conducted clinical studies on ACH, and to alert the public health authorities. Future observational studies should have standardized outcomes measures such as mortality, physical comorbidities, humanistic outcomes, and socioeconomic and environmental burden outcomes.